Implantable medical device with beneficial agent concentration gradient

ABSTRACT

The implantable medical devices are configured to release at least one therapeutic agent from a matrix affixed to the implantable body with a release profile which is programmable to the agent and treatment. The matrix is formed such that the concentration of the therapeutic agent in the matrix varies as a gradient relative to a surface of the implantable body. The change in the concentration gradient of the agent in the matrix directly controls the rate of elution of the agent from the matrix. The therapeutic agent matrix can be disposed in the stent or on surfaces of the stent in various configurations, including within volumes defined by the stent, such as openings, holes, or concave surfaces, as a reservoir of agent, and alternatively as a coating on all or a portion of the surfaces of the stent structure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/369,592 filed on Mar. 7, 2006, which is a divisional of U.S. patentapplication Ser. No. 10/777,283, filed Feb. 11, 2004, abandoned, whichis a Continuation-in-Part of U.S. patent application Ser. No. 10/402,893filed on Mar. 28, 2003, now U.S. Pat. No. 7,056,338, issued Jun. 6,2006, all of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to a therapeutic agent delivery device which has aconcentration gradient of the therapeutic agent contained within amatrix to provide release kinetics which are specifically programmablefor the particular agent, administration period, and release ratedesired.

BACKGROUND

Implantable medical devices are sometimes used for delivery of atherapeutic agent, such as a drug, to an organ or tissue in the body. Itis hoped that these devices may deliver agents to a wide variety ofbodily systems to provide a wide variety of treatments.

One implantable medical device which has been used for local delivery oftherapeutic agents is the coronary stent. Coronary stents are typicallyintroduced percutaneously, and transported transluminally untilpositioned at a desired location. These devices are then expanded eithermechanically, such as by the expansion of a mandrel or balloonpositioned inside the device, or expand themselves by releasing storedenergy upon actuation within the body. Once expanded within the lumen,these devices, called stents, become encapsulated within the body tissueand remain a permanent implant.

Of the many problems that may be addressed through stent-based localdelivery of therapeutic agents, one of the most important is restenosis.Restenosis is a major complication that can arise following vascularinterventions such as angioplasty and the implantation of stents. Simplydefined, restenosis is a wound healing process that reduces the vessellumen diameter by extracellular matrix deposition, neointimalhyperplasia, and vascular smooth muscle cell proliferation, and whichmay ultimately result in renarrowing or even reocclusion of the lumen.Despite the introduction of improved surgical techniques, devices, andpharmaceutical agents, the overall restenosis rate is still reported inthe range of 25% to 50% within six to twelve months after an angioplastyprocedure. To treat this condition, additional revascularizationprocedures are frequently required, thereby increasing trauma and riskto the patient.

One of the techniques under development to address the problem ofrestenosis is the use of surface coatings of various therapeutic agentson stents. U.S. Pat. No. 5,716,981, for example, discloses a stent thatis surface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). Known surface coatings, however, can providelittle actual control over the release kinetics of therapeutic agents.These coatings are generally very thin, typically 5 to 8 microns deep.The surface area of the stent, by comparison is very large, so that theentire volume of the therapeutic agent has a very short diffusion pathto discharge into the surrounding tissue. The ability to shape therelease profiles from such systems is severely limited.

Accordingly, it would be desirable to provide a therapeutic agentdelivery device with the ability to program the release kinetics to theparticular agent, administration period, and release rate desired.

SUMMARY OF THE INVENTION

The present invention relates to implantable medical devices forprogrammable delivery of a therapeutic agent, methods of formingimplantable medical devices, and methods for delivering therapeuticagents from implantable medical devices.

In accordance with one aspect of the invention, an implantable medicaldevice configured to release at least one therapeutic agent therefrom isprovided, wherein the device includes an implantable body and a matrixaffixed to the implantable body. The matrix contains the at least onetherapeutic agent therein, and the matrix is formed such that theconcentration of the therapeutic agent in the matrix varies as acontinuous gradient relative to a surface of the implantable body.

In accordance with another aspect of the invention, a method of formingan implantable medical device configured to release at least onetherapeutic agent therefrom is provided. The therapeutic agent isdisposed in a matrix affixed to the body of the implantable medicaldevice, and the concentration of the at least one therapeutic agent inthe matrix varies as a continuous gradient relative to a surface of thebody of the implantable medical device. The method involves forming afirst homogeneous solution comprising the at least one therapeutic agentmixed with a polymeric binder, applying the first homogeneous solutionto the body of the implantable medical device, solidifying the firsthomogeneous solution, thereby forming a first portion of the matrix,forming a second homogeneous solution comprising the polymeric binder,applying the second homogeneous solution to the first portion of thematrix, thereby at least partially liquifying the first portion of thematrix, and solidifying the second homogeneous solution, thereby forminga second portion of the matrix, wherein the concentration of the atleast one therapeutic agent in the matrix is different in the first andsecond portions of the matrix.

In accordance with an additional aspect of the invention, a method offorming an implantable medical device configured to release at least onetherapeutic agent therefreom is provided. The therapeutic agent isdisposed in a matrix affixed to a body of the implantable medicaldevice, and a concentration of the at least one therapeutic agent in thematrix varies as a continuous gradient relative to a surface of theimplantable medical device body. The method involves forming ahomogeneous solution comprising a polymeric binder and a solvent,evaporating the solvent in the homogeneous solution, thereby forming amatrix, exposing the matrix to a solution comprising the therapeuticagent for a time sufficient to produce a partial diffusion of thetherapeutic agent into the matrix such that the concentration of thetherapeutic agent varies in the matrix, and affixing the matrix to theimplantable medical device body.

In accordance with a further aspect of the invention, a method fortreating a patient by local delivery of at least one therapeutic agentis provided. The method involves delivering an implantable medicaldevice into the body of a patient, the implantable medical device havinga matrix affixed to a body of the implantable medical device withconcentration of the at least one therapeutic agent in the matrixvarying as a continuous gradient relative to a surface of the body ofthe implantable medical device. The method further involves deliveringthe therapeutic agent at a release rate and over an administrationperiod determined by the gradient of therapeutic agent in the matrix.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a perspective view of one example of a stent according to thepresent invention.

FIG. 2 is a side view of a portion of the stent of FIG. 1.

FIG. 3 is a side cross sectional view of an example of an opening in astent showing a matrix with one therapeutic agent having a concentrationgradient.

FIG. 4 is a graph of the therapeutic agent concentration gradient ofFIG. 3.

FIG. 5 is a graph of the release kinetics of the stent of FIG. 3.

FIG. 6 is a side cross sectional view of another example of an openingin a stent matrix with one therapeutic agent having a concentrationgradient.

FIG. 7 is a graph of the therapeutic agent concentration gradient ofFIG. 6.

FIG. 8 is a graph of the release kinetics of the stent of FIG. 6.

FIG. 9 is a side cross sectional view of an example of an opening in astent showing a matrix with two therapeutic agents having concentrationgradients.

FIG. 10 is a graph of the therapeutic agent concentration gradients ofFIG. 9.

FIG. 11 is a graph of the release kinetics of the stent of FIG. 9.

DETAILED DESCRIPTION

The invention relates to a medical device or stent having a matrixcontaining a therapeutic agent therein such that the concentration ofagent in the matrix varies as a function of the position relative to thematrix surfaces. The agent may be any therapeutic agent that provides abeneficial effect after the deployment of the medical device and releaseof the agent from the matrix into the tissue of a mammal.

First, the following terms, as used herein, shall have the followingmeanings:

The terms “drug” and “therapeutic agent” are used interchangeably torefer to any therapeutically active substance that is delivered to aliving being to produce a desired, usually beneficial, effect.

The term “matrix” or “biocompatible matrix” are used interchangeably torefer to a medium or material that, upon implantation in a subject, doesnot elicit a detrimental response sufficient to result in the rejectionof the matrix. The matrix typically does not provide any therapeuticresponses itself, though the matrix may contain or surround atherapeutic agent, and/or modulate the release of the therapeutic agentinto the body. A matrix is also a medium that may simply providesupport, structural integrity or structural barriers. The matrix may bepolymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic,amphiphilic, and the like. The matrix may be bioresorbable ornon-bioresorbable.

The term “bioresorbable” refers to a matrix, as defined herein, that canbe broken down by either chemical or physical process, upon interactionwith a physiological environment. The matrix can erode or dissolve. Abioresorbable matrix serves a temporary function in the body, such asdrug delivery, and is then degraded or broken into components that aremetabolizable or excretable, over a period of time from minutes toyears, preferably less than one year, while maintaining any requisitestructural integrity in that same time period.

The term “openings” includes both through openings and recesses.

The term “pharmaceutically acceptable” refers to the characteristic ofbeing non-toxic to a host or patient and suitable for maintaining thestability of a therapeutic agent and allowing the delivery of thetherapeutic agent to target cells or tissue.

100311 The term “polymer” refers to molecules formed from the chemicalunion of two or more repeating units, called monomers. Accordingly,included within the term “polymer” may be, for example, dimers, trimersand oligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000. Examples of polymers include but are not limited to,poly-α-hydroxy acid esters such as, polylactic acid (PLLA or DLPLA),polyglycolic acid, polylactic-co-glycolic acid (PLGA), polylacticacid-co-caprolactone; poly (block-ethyleneoxide-block-lactide-co-glycolide) polymers (PEO-block-PLGA andPEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene oxide,poly (block-ethylene oxide-block-propylene oxide-block-ethylene oxide);polyvinyl pyrrolidone; polyorthoesters; polysaccharides andpolysaccharide derivatives such as polyhyaluronic acid, poly (glucose),polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, cyclodextrins and substituted cyclodextrins,such as beta-cyclodextrin sulfobutyl ethers; polypeptides and proteins,such as polylysine, polyglutamic acid, albumin; polyanhydrides;polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxybutyrate, and the like.

The term “primarily” with respect to directional delivery, refers to anamount greater than about 50% of the total amount of therapeutic agentprovided to a blood vessel.

The term “restenosis” refers to the renarrowing of an artery followingan angioplasty procedure which may include stenosis following stentimplantation.

The term “liquefied” is used herein to define a component which is putin a liquid state either by heating the component to a temperaturehigher than its melting point, or glass transition temperature, or bydissolving the component in a solvent. The typical liquefied materialsof the present invention will have a viscosity of less than about 10,000centipoise, and preferably less than about 1,000 centipoise, and morepreferably less than about 100 centipoise.

The term “homogeneously disposed” refers to a mixture in which each ofthe components are uniformly dispersed within the matrix.

The term “heterogeneously disposed” refers to a mixture in which thecomponents are not mixed uniformly into a matrix.

FIG. 1 illustrates one example of an implantable medical device in theform of a stent 10. Although the present invention will be describedwith reference to a stent, the invention can also be useful as othertypes of drug delivery implants including subcutaneous implants,embolization devices, and implants for delivery of chemotherapeuticagents.

FIG. 2 is an enlarged flattened view of a portion of the stent of FIG. 1illustrating one example of a stent structure including struts 12interconnected by ductile hinges 20. The struts 12 include openings 14which can be non-deforming openings containing the therapeutic agent andmatrix. One example of a stent structure having non-deforming openingsis shown in U.S. Pat. No. 6,562,065 which is incorporated herein byreference in its entirety.

The implantable medical devices of the present invention are configuredto release at least one therapeutic agent from a matrix affixed to theimplantable body. The matrix is formed such that the concentration ofthe therapeutic agent in the matrix varies as a gradient relative to asurface of the matrix affixed to the implantable body. The deposition ofa coating on a surface, such as by dipping or spraying may result in thephenomenon know as blooming by which the drug migrates to the surfaceresulting in increased concentration at the matrix surface. However,known coating methods do not achieve configurations in which aconcentration in an area adjacent the matrix surface is less than aconcentration of the drug at another part of the matrix. The presentinvention provides methods and devices by which an implantable medicaldevice can be designed to achieve a particular release profile byproviding a concentration gradient of drug in a homogeneous polymermatrix in which the concentration gradient is provided other than by thephenomenon of blooming.

In one embodiment, the matrix is a polymeric material which acts as abinder or carrier to hold the agent in or on the stent and/or modulatethe release of the agent from the stent. The polymeric material can be abioresorbable or a non-bioresorbable material.

The therapeutic agent containing matrix can be disposed in the stent oron surfaces of the stent in various configurations, including withinvolumes defined by the stent, such as openings, holes, or concavesurfaces, as a reservoir of agent, and alternatively as a coating on allor a portion of surfaces of the stent structure. When the therapeuticagent matrix is disposed within openings in the strut structure of thestent to form a reservoir, the openings may be partially or completelyfilled with matrix containing the therapeutic agent.

The concentration of agent in a local region of the matrix is the sum ofthe amount of agent dissolved in the matrix, in a so-called solidsolution morphology, and the amount dispersed in that local region ofthe matrix, a so-called solid emulsion morphology. The relative amountof dissolved and dispersed agent in a region is controlled by thesolubility of the agent in the matrix material. When the limit ofsolubility of the agent in the matrix material is reached, anyadditional agent will be in a dispersed second phase particulatemorphology.

FIG. 3 is a cross section of the stent 10 and blood vessel 100illustrating one example of an opening 14 arranged adjacent the vesselwall with a mural surface 26 abutting the vessel wall and a luminalsurface 24 opposite the mural surface. The opening 14 of FIG. 3 containsa matrix 40 with a therapeutic agent illustrated by Os in the matrix. Ascan be seen in the example of FIG. 3, the concentration of thetherapeutic agent (Os) is highest at the luminal side of the matrix 40and lowest at the mural side of the matrix. The luminal side 24 of thestent 10 is also provided with a barrier layer 30. The barrier layer 30causes the therapeutic agent to be delivered primarily to the mural side26 of the stent.

FIG. 4 illustrates graphically a concentration gradient similar to thatdepicted in FIG. 3 where the agent concentration in the matrix ishighest in the middle of the stent or adjacent the luminally locatedbarrier layer 30 and the agent concentration decreases moving toward themural side of the matrix. The concentration gradient is described by thelocal concentration of the agent in matrix regions along a theoreticalline substantially perpendicular to the surfaces of the matrix. Acontinuous agent concentration gradient is where the agent concentrationin a volume of matrix varies in a blended fashion in moving betweensuccessive positions along the line substantially perpendicular to thematrix surface. Thus, if the matrix surface was substantially collinearwith the stent surface and the matrix was sliced into a plurality ofslices substantially parallel to the stent surface, the adjacent sliceswill have different agent concentrations. Alternately, the matrixsurface may be contoured and the adjacent slices may be similarlyconfigured.

As illustrated in FIG. 3, the barrier layer 30 includes no therapeuticagent and the concentration gradient of therapeutic agent is provided inthe matrix in the portion of the opening 14 not containing the barriermaterial. Alternatively, the barrier layer 30 may include sometherapeutic agent and the concentration gradient may continue in part orall of the barrier layer.

As shown in FIG. 4, the change in agent concentration in the matrix is acontinuous function of the position relative to the matrix surfaces. Asshown in FIG. 5, the release kinetics of the system of FIGS. 3 and 4 canbe essentially linear (essentially constant release rate over time)after an initial release. Such substantially linear release profiles aredescribed in further detail in U.S. patent application Ser. No.10/777,881 filed on Feb. 11, 2004 which is incorporated herein byreference in its entirety.

FIG. 6 illustrates a configuration of a matrix 50 in an opening 14 wherethe matrix and therapeutic agent concentration gradient are designed forrapid initial release of agent to the luminal side followed by a lowlevel release for an extended time. The agent concentration in FIG. 6 ishigh at the luminal surface 24 of the matrix 50 and the concentrationgradient will decrease steeply in the interior of the matrix. FIG. 7illustrates the concentration gradient of the FIG. 6 examplegraphically. FIG. 8 illustrates the agent release over time for theexample of FIGS. 6 and 7. Using careful specification of the agentconcentration gradient in this example, substantially first order agentrelease kinetics with directionally controlled delivery may be obtained.

Since the matrix is created in a stepwise manner, as will be describedbelow, individual chemical compositions and pharmacokinetic propertiescan be imparted to different areas of the matrix. Numerous usefularrangements of such matrix areas can be formed, some of which will bedescribed herein. Each of the areas of the matrix may include one ormore agents in the same or different proportions from one area to thenext. The matrix may be solid, porous, or filled with other drugs orexcipients. The agents may be homogeneously disposed or heterogeneouslydisposed in different areas of the matrix.

FIG. 9 illustrates an example of another stent 10 having a matrix 60containing two agents with different concentration gradients. In FIG. 9,a first agent (Drug A) represented by Os has a concentration gradientwith a maximum concentration at a luminal side 24 of the stent. A secondagent (Drug B) represented by ▾s has a concentration gradient with amaximum concentration at a mural side of the matrix. This configurationresults in the delivery of two drugs in different primary deliverydirections. For example, an antithrombotic agent (Drug A) may bedelivered primarily luminally at a relatively quick initial release ratewhile an antirestenotic agent (Drug B) is delivered primarily murallywith a different delivery profile having a more constant release rateand longer administration period. FIG. 10 illustrates graphically theagent concentration gradients of the first agent (Drug A) and the secondagent (Drug B). FIG. 11 illustrates the cumulative release of the firstand second agents (Drug A and Drug B) over time.

It is envisioned that the continuous agent concentration gradient willtake a variety of forms depending on the desired administration periodand rate of elution of the agent into the tissue surrounding the stent,as well as the desired direction of elution of agent from the stent,either mural or luminal. FIGS. 3-11 are merely illustrative of some ofthe concentration gradients which are useful. Further combinations oftwo or more agents with independent concentration gradients can providea range of controlled release kinetic profiles of the agents from thematrix in or on the stent.

Therapeutic Agents

Some of the therapeutic agents for use with the present invention whichmay be transmitted primarily luminally, primarily morally, or bothinclude, but are not limited to, antiproliferatives including paclitaxeland rapamycin, antithrombins, immunosuppressants including sirolimus,antilipid agents, anti-inflammatory agents, antineoplastics,antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins,antimitotics, metalloproteinase inhibitors, NO donors, estradiols,anti-sclerosing agents and vasoactive agents, endothelial growthfactors, estrogen, beta blockers, AZ blockers, hormones, statins,insulin growth factors, antioxidants, membrane stabilizing agents,calcium antagonists, retinoid, bivalirudin, phenoxodiol, etoposide,ticlopidine, dipyridamole, and trapidil alone or in combinations withany therapeutic agent mentioned herein. Therapeutic agents also includepeptides, lipoproteins, polypeptides, polynucleotides encoding peptides,lipids, protein-drugs, protein conjugate drugs, enzymes,oligonucleotides and their derivatives, ribozymes, other geneticmaterial, cells, antisense, oligonucleotides, monoclonal antibodies,platelets, prions, viruses, bacteria, and eukaryotic cells such asendothelial cells, stem cells, ACE inhibitors, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. The therapeuticagent may also be a pro-drug, which metabolizes into the desired drugwhen administered to a host. In addition, therapeutic agents may bepre-formulated as microcapsules, microspheres, microbubbles, liposomes,niosomes, emulsions, dispersions or the like before they areincorporated into the therapeutic layer. Therapeutic agents may also beradioactive isotopes or agents activated by some other form of energysuch as light or ultrasonic energy, or by other circulating moleculesthat can be systemically administered. Therapeutic agents may performmultiple functions including modulating angiogenesis, restenosis, cellproliferation, thrombosis, platelet aggregation, clotting, andvasodilation.

Anti-inflammatories include but are not limited to non-steroidalinti-inflammatories (NSAID), such as aryl acetic acid derivatives, e.g.,Diclofenac; aryl propionic acid derivatives, e.g., Naproxen; andsalicylic acid derivatives, e.g., Diflusinal. Anti-inflammatories alsoinclude glucocoriticoids (steroids) such as dexamethasone, aspirin,prednisolone, triamcinolone, pirfenidone, meclofenamic acid, tranilast,and nonsteroidal anti-inflammatories. Anti-inflammatories may be used incombination with antiproliferatives to mitigate the reaction of thetissue to the antiproliferative.

The agents can also include anti-lymphocytes; anti-macrophagesubstances; cyclooxygenase inhibitors; immunomodulatory agents;anti-oxidants; cholesterol-lowering drugs; statins and angiotens inconverting enzyme (ACE); fibrinolytics; inhibitors of the intrinsiccoagulation cascade; antihyperlipoproteinemics; and anti-plateletagents; anti-metabolites, such as 2-chlorodeoxy adenosine (2-CdA orcladribine); immuno-suppressants including sirolimus, everolimus,tacrolimus, etoposide, and mitoxantrone; anti-leukocytes such as 2-CdA,IL-1 inhibitors, anti-CD116/CD18 monoclonal antibodies, monoclonalantibodies to VCAM or ICAM, zinc protoporphyrin; anti-macrophagesubstances such as drugs that elevate NO; cell sensitizers to insulinincluding glitazones; high density lipoproteins (HDL) and derivatives;and synthetic facsimile of HDL, such as lipator, lovestatin,pranastatin, atorvastatin, simvastatin, and statin derivatives;vasodilators, such as adenosine, and dipyridamole; nitric oxide donors;prostaglandins and their derivatives; anti-TNF compounds; hypertensiondrugs including Beta blockers, ACE inhibitors, and calcium channelblockers; vasoactive substances including vasoactive intestinalpolypeptides (VIP); insulin; cell sensitizers to insulin includingglitazones, P par agonists, and metformin; protein kinases; antisenseoligonucleotides including resten-NG; antiplatelet agents includingtirofiban, eptifibatide, and abciximab; cardio protectants including,VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-Imilano, amlodipine, nicorandil, cilostaxone, and thienopyridine;cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors; andpetidose inhibitors which increase glycolitic metabolism includingomnipatrilat. Other drugs which may be used to treat inflammationinclude lipid lowering agents, estrogen and Adiponectin.

Agents may also be delivered using a gene therapy-based approach incombination with an expandable medical device. Gene therapy refers tothe delivery of exogenous genes to a cell or tissue, thereby causingtarget cells to express the exogenous gene product. Genes are typicallydelivered by either mechanical or vector-mediated methods.

Some of the agents described herein may be combined with additives whichpreserve their activity. For example additives including surfactants,antacids, antioxidants, and detergents may be used to minimizedenaturation and aggregation of a protein drug. Anionic, cationic, ornonionic detergents may be used. Examples of nonionic additives includebut are not limited to sugars including sorbitol, sucrose, trehalose,dextrans including dextran, carboxymethyl (CM) dextran, diethylaminoetyl (DEAE) detran; sugar derivatives including D-glucosaminic acid, andD-glucose diethyl mercaptal, synthetic polyethers including polyethyleneglycol (PEG and PEO) and polyvinyl pyrrolidone (PVP); carboxylic acidsincluding D-lactic acid, glycolic acid, and propionic acid; detergentswith affinity for hydrophobic interfaces includingn-dodecyl-β-D-maltoside, n-ocyl-β-D-glucoside, PEO-fatty acid esters(e.g. stearate (myrj 59) or oleate), PEO-sorbitan-fatty acid esters(e.g. Tween 80, PEO-20 sorbitan monooleate), sorbitan-fatty acid esters(e.g. SPAN 60, sorbitan monostearate), PEO-glyceryl-fatty acid esters;glyceryl fatty acid esters (e.g. glyceryl monostearate),PEO-hydrocarbon-esters (e.g., PEO-10 oleyl ether; triton X-100; andLubrol. Examples of ionic detergents include but are not limited tofatty acid salts including calcium stearate, magnesium stearate, andzinc stearate; phospholipids including lecithin and phosphatidylcholine; CM-PEG; cholic acid; sodium dodecyl sulfate (SDS); docusate(AOT); and taumocholic acid.

Matrix Formation Methods

The agent matrix structure with the agent concentration gradient can beformed by several methods. According to one method, agent and polymermaterial are together converted into agent matrix reservoirs with anagent concentration gradient structure by first creating a homogeneoussolution of agent and polymer carrier in a liquid form, such as in asolvent. One example of a solvent is one in which all agent and polymerare fully soluble at the respective concentrations desired forprocessing such that all ingredients are molecularly dissolved in thesolvent.

Solvents may be water based, as when water soluble agents and watersoluble polymers are the components of the agent delivery matrix.Alternatively, solvents can be mixtures of water with miscible organicsolvents, such as dimethyl sulfoxide (DMSO), Nmethyl pyrrolidone (NMP),ethyl lactate (EL), dimethyl acetamide (DMAc), or simple alcohols.Additionally, non-aqueous solvents, predominantly organic solvents, canbe suitable for non-water soluble polymers, such aspoly(lactide-co-glycolide) polymers (PLGAs). Example organic solventsinclude DMSO, NMP, EL, anisole, chloroform, tetrahydrofuran (THF),xylene, and methylene chloride.

In the first method, steps (i) and (ii) are preformed followed by steps(iii) and (iv) which are repeated until the desired concentrationgradient structure is obtained:

-   -   i) a solution comprised of suitable solvent and polymer        material, and optionally a therapeutic agent, is introduced into        an opening on the stent;    -   ii) the solvent is evaporated from the solution to form a first        portion of matrix;    -   iii) a second solution is introduced which partially dissolves        of otherwise liquifies the precedent material from step (ii) and        allows partial mixing of the agent of precedent material and the        components of the second solution to create a new hybrid        solution in the cavity or hole in the stent; and    -   iv) the solvent is evaporated from the newly formed hybrid        solution to provide a portion of matrix having a concentration        gradient of the agent therein. By changing the composition of        successive solutions there will result a final agent containing        matrix where the agent is present in a continuously changing        concentration relative to the depth of the matrix, termed a        concentration gradient.

Although the process has been described employing a solvent, a similarprocess may use a solution without a solvent when the polymer is heatedto achieve a liquefied or flowable condition.

Two general sequences of solution compositions can provide theconcentration gradient structure of the invention. In a first sequence,one or several iterations of the same agent and polymer compositions areintroduced as described followed by successive iterations of solutionscontaining polymer only. In this manner a first portion of matrix isfabricated with an agent containing solution followed by introduction ofa second portion of matrix without agent. The second portion of matrixwithout the agent introduced just after the first portion containingagent will extract a portion of agent from the first portion intoitself, creating a concentration gradient of the agent in the combinedstructure after the solvent has evaporated. Successive additions ofsolutions with polymer and no agent will only be able to dissolve theportion formed just before, which has successively smaller amounts ofagent, so as the depth of the matrix is increased by successiveadditions the agent proportion will be successively decreasing,continuing the formation of an agent concentration gradient.

Although the first method has been described with reference todepositing in a hole or cavity, the matrix may also be formed on thestent or in the stent in other configurations including coatings orpartial coatings in substantially the same manner. Coatings aregenerally less preferable than reservoirs, as the depth of reservoirspermits more complex morphologies.

In a second sequence, a first series of iterations are done with asolution containing matrix and an agent at a first agent concentration,followed by a second series of iterations done with a solution havingmatrix and the agent at a second agent concentration. The resultantmatrix will have a agent concentration gradient where the absoluteconcentration is near the first concentration at one side of the matrix,at an intermediate concentration in the middle of the matrix, and nearthe second agent concentration at the opposite side of the matrix.

In a second method an agent concentration gradient is formed in thematrix by a process of diffusion. A matrix containing no agent is firstprepared from solutions containing polymer. The formed matrix is thenimmersed in a solution containing an agent for a time period to allow apartial diffusion of the agent from the solution into the matrix, thenthe matrix is removed from the solution. The resultant matrix will havea relatively higher agent concentration near the surface(s) thatcontacted the solution and lower concentration toward the opposite side,thus forming an agent concentration gradient across the depth of theagent containing matrix.

This second method can be performed with a matrix in the form of acoating on a stent or a partial coating on a stent, with a matrix withinopenings in a stent, a matrix prior to placing the matrix on or in thestent, or another matrix configuration. When the matrix is formed withinopenings in a stent a barrier layer may be placed on one side of theopening to allow diffusion of the agent into the matrix from primarilyone side of the opening. The barrier layer may subsequently be removedif delivery from the barrier side is desired. Additional barrier layersmay be added after formation of the concentration gradient if desired.The barrier layer can be a bioresorbable or non-bioresorbable.

EXAMPLE 1 Formulation Comprising a Gradient of a Therapeutic Agent

In the example below, the following abbreviations have the followingmeanings.

-   -   PLGA=poly(lactide-co-glycolide)    -   DMSO=Dimethyl sulfoxide    -   NMP=N-methylpyrrolidone    -   DMAC=Dimethyl acetamide

A first mixture of high molecular weight PLGA and a suitable organicsolvent, such as DMSO, NMP, or DMAC 93% wt. is prepared. The mixture isloaded dropwise into openings in the stent, then the solvent isevaporated to begin formation of the barrier layer. A one or moreadditional barrier layers are laid over the first by the same method offilling polymer solution into the hole followed by solvent evaporation.

A second mixture of paclitaxel and low molecular weight PLGA, in asuitable organic solvent, such as DMSO, is introduced into openings inthe stent over the barrier layer. The solvent is evaporated to form adrug filled therapeutic agent layer. The filling and evaporationprocedure is repeated until the hole is filled to about 50% of its totalvolume with drug in therapeutic agent layer layered on top of thebarrier layer.

Multiple layers of a third solution, of low molecular weight PLGA and asuitable organic solvent, such as DMSO, are then laid down over thetherapeutic agent layer to form the concentration gradient. When each ofthe third solution layers is loaded into the stent, a portion of thelayer beneath is incorporated in the new layer. In this way the matrixis formed containing a concentration gradient of paclitaxel agent.

Following implantation of the filled stent in vivo, the paclitaxelcontained within the stent is delivered slowly over a time period ofabout 5 to about 60 days, preferably about 10 to about 30 days. Thebarrier layer prevents the therapeutic agent from being delivered outthe barrier layer side of openings in the stent. The barrier layercompletely degrades after the administration of the paclitaxel.

While the invention has been described in detail with reference to thepreferred embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made and equivalentsemployed, without departing from the present invention.

1. A method of forming an implantable medical device configured torelease at least one therapeutic agent therefrom, the method comprising:providing an implantable medical device having a body, a luminalsurface, a mural surface and at least one recess in the body; forming afirst homogeneous solution comprising the at least one therapeutic agentmixed with a polymeric binder; introducing the first homogeneoussolution into the at least one recess in the body of the implantablemedical device; solidifying the first homogeneous solution, therebyforming a first portion of a matrix, wherein a concentration of the atleast one therapeutic agent in the matrix varies as a continuousgradient relative to a surface of the body of the implantable medicaldevice; forming a second homogeneous solution comprising the polymericbinder; applying the second homogeneous solution to the first portion ofthe matrix, thereby at least partially liquifying the first portion ofthe matrix; and solidifying the second homogeneous solution, therebyforming a second portion of the matrix, wherein the concentration of theat least one therapeutic agent in the matrix is higher at the luminalsurface of the implantable body than at the mural surface of theimplantable body.
 2. The method of claim 1, wherein the first and secondhomogenous solutions include a solvent and the first and secondhomogenous solutions are solidified by evaporation of the solvent. 3.The method of claim 2, wherein the solvent comprises a miscible organicsolvent.
 4. The method of claim 3, wherein the miscible organic solventis selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, ethyl lactate, and simple alcohols.
 5. The method of claim2, wherein the solvent and the polymeric binder are both non-watersoluble.
 6. The method of claim 5, wherein the non-water soluble solventis selected from the group consisting of a poly(lactide-co-glycolide)polymer, N-methyl pyrrolidone, ethyl lactate, anisole, chloroform,tetrahydrofuran, xylene, and methylene chloride.
 7. The method of claim1, further comprising: applying successive homogeneous solutions to thematrix; and solidifying the successive homogeneous solutions, therebyforming additional portions of the matrix, wherein the concentration ofthe therapeutic agent in the matrix is different in the successiveportions of the matrix.
 8. The method of claim 1, wherein said at leastone recess extends through the body of the implantable medical device.9. The method of claim 1, wherein the polymeric binder of the firsthomogeneous solution is water soluble.
 10. The method of claim 1,wherein the therapeutic agent is selected from the group consisting ofantithrombotic agents, antiproliferative agents, and antirestenoticagents.
 11. The method of claim 1, wherein the matrix is selected fromthe group consisting of poly(lactide-co-glycolide) (PLGA) and Polyvinylpyrrolidone (PVP).
 12. The method of claim 1, further comprising:applying a solution of a barrier material prior to applying introducingthe first homogenous solution, the barrier material forming a barrier tothe passage of the therapeutic agent in the first homogenous solution toone side of the body of the implantable medical device.
 13. The methodof claim 1, wherein the second homogenous solution contains notherapeutic agent.
 14. The method of claim 1, wherein the secondhomogeneous solution comprises the at least one therapeutic agent, andwherein a concentration of the at least one therapeutic agent in thesecond homogeneous solution is different from a concentration of the atleast one therapeutic agent in the first homogeneous solution.
 15. Themethod of claim 1, wherein the implantable medical device is a stent.16. The method of claim 14, further comprising: applying successivehomogeneous solutions to the matrix; and solidifying the successivehomogeneous solutions, thereby forming additional portions of thematrix, wherein the concentration of the at least one therapeutic agentin the matrix is different in the successive portions of the matrix. 17.A method of forming an implantable medical device configured to releaseat least one therapeutic agent therefrom, the method comprising:providing an implantable medical device having a substantiallycylindrical body, a luminal surface, a mural surface and a plurality ofstruts; forming a homogeneous solution comprising a polymeric binder anda solvent; evaporating the solvent in the homogeneous solution, therebyforming a matrix; exposing the matrix to a solution comprising thetherapeutic agent for a time sufficient to produce a partial diffusionof the therapeutic agent into the matrix wherein a concentration of theat least one therapeutic agent in the matrix varies as a continuousgradient; and affixing the matrix to the body of the implantable medicaldevice body such that the matrix is disposed in the plurality of holespassing through at least some of the struts in the implantable body; andcoating the matrix with a barrier layer at the luminal surface, whereinthe therapeutic agent has a maximum concentration substantially adjacentto the barrier layer and a minimum concentration substantially adjacentto the mural surface of the implantable body.
 18. The method of claim17, wherein the matrix is affixed to the implantable medical device bodyby placing the matrix into the body prior to immersing the matrix in thesolution comprising the therapeutic agent.
 19. The method of claim 17,wherein the matrix is affixed to the implantable medical device body bydisposing the homogeneous solution comprising a polymeric binder and asolvent into the plurality of openings and then evaporating the solvent.20. The method of claim 17, wherein the implantable medical device is astent.